Resuscitation from sudden cardiac arrest (SCA) is typically initiated in patients with ongoing ischemia and ventricular fibrillation (VF) or tachycardia (VT) that, even if successful, is commonly followed by repeated rearrest. Despite significant efforts to improve resuscitation from SCA, survival remains poor prompting NIH to identify resuscitation as a high priority for emergency care research. Beat-to-beat alternans of cellular repolarization in the myocardium (repolarization alternans) is a substrate for arrhythmias, is rampant during resuscitation, and is manifested on the ECG as T-wave oscillations that can alternate (2:1) or as more complex oscillations. In preliminary studies, we observed in resuscitation patients and in an in vivo translational model of resuscitation from SCA, that rearrest due to VT/VF is preceded by T-wave oscillations that are complex; whereas, rearrest due to pulseless electrical activity (PEA) is preceded by increased T-wave oscillations that alternate. Accordingly, we contend that when T-wave oscillations are complex, repolarization alternans in the myocardium is spatially discordant, which is repolarization alternans occurring out-of-phase in adjacent regions and is highly arrhythmogenic. In contrast, when T-wave oscillations alternate, repolarization alternans in the myocardium is spatially in-phase (concordant), which poses no known immediate arrhythmia risk but is associated with mechanical dysfunction and, thus, PEA. Finally, in the absence of any repolarization alternans, risk of rearrest due to PEA or VT/VF is low. We hypothesize that during resuscitation rearrest due to VT/VF or PEA is strongly linked to repolarization alternans in the myocardium that is spatially discordant or not, respectively, and that specifically targeting the underlying mechanisms can prevent rearrest due to VT/VF and, possibly, PEA. In addition, the full spectrum of ECG T-wave oscillations can be utilized to predict no rearrest and rearrest from VT/VF or PEA and, thus, be used in the future as a biomarker to guide therapy and significantly improve outcomes. Our hypotheses will be tested with the following aims. 1) Determine the mechanistic relationship between cellular repolarization alternans and rearrest due to VT/VF or PEA in an in vivo model of resuscitation. 2) Determine if targeting the mechanisms of repolarization alternans can prevent rearrest during resuscitation, thereby gaining additional mechanistic insight. 3) Develop and test an ECG biomarker for predicting risk of rearrest due to VT/VF and PEA in resuscitation patients. To achieve these aims, we will utilize sophisticated instrumentation and signal processing in an in vivo translational model of resuscitation as well as in pre-hospital and in- hospital resuscitation patients. We have also established a highly translational collaboration that combines expertise in emergency medicine, cardiac arrhythmia, and clinical electrophysiology. Our scientific environment provides a unique opportunity to develop a better understanding of arrhythmia mechanisms relevant to resuscitation in order to develop novel and effective therapies.